Method of preparing 4a-arylhexahydro-1H-2-pyrindines and 4a-aryloctahydroisoquinolines

ABSTRACT

4a-Arylhexahydro-1H-2-pyrindines and 4a-aryloctahydroquinolines analgesic agonists and antagonists are prepared doubly alkylating a 4-aryltetrahydropyridine with an α,ω-dihaloalkane.

This is a division of application Ser. No. 50,940 filed June 21, 1979,now U.S. Pat. No. 4,236,009, issued Nov. 25, 1980.

BACKGROUND OF THE INVENTION

4a-Phenyl(or substituted phenyl)octahydro-1H-2-pyrindines are disclosedin Belgian Pat. No. 860,314 as being useful analgesic agents havingmixed agonist-antagonist properties. These compounds can be representedby the following formula: ##STR1## wherein R is H, (C₁ -C₈)alkyl etc.and R¹ is H, alkoxy, OH or alkanoyloxy.4a-Phenyloctahydro-1H-2-pyrindines of the above formula can be preparedby the following reaction sequence: A 2-arylcyclohexanone is alkylatedat the 2-position by reaction with an α-halo acetate in the presence ofbase. The product of this reaction, a2-aryl-2-alkoxycarbonylmethylcyclohexanone, is next formylated at the6-position by reaction with ethyl formate in the presence of metallicsodium. The 2-aryl-2-alkoxycarbonylmethyl-6-formylcyclohexanone thusprepared is next reacted with p-tosylazide to provide a2-aryl-2-alkoxycarbonylmethyl-6-diazocyclohexanone. Photolysis of thediazo compound results in a ring contraction, the product of thereaction being a2-aryl-2-alkoxycarbonylmethyl-1-methoxycarbonylcyclopentane. Hydroxylsisof this compound provides the corresponding diacid,2-aryl-2-hydroxycarbonylmethyl-1-hydroxycarbonylcyclopentane.Cyclization of this diacid derivative with an acid halide such as acetylchloride provides the corresponding anhydride, a4a-aryl-tetrahydro-2,6-dioxocyclopenta[c]pyran. Reaction of thisdioxopyran with ammonia or a primary amine (R² -NH₂) yields a cyclicimide; to wit, a1,3-dioxo-4a-aryl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. Thedioxopyrindine can then be reduced as with lithium aluminum hydride toyield a 4a-aryl-octahydro-1H-2-pyrindine of formula I. If the product ofthe synthesis produces a secondary amine, (R is H), other N-derivativescan be prepared as follows:

The secondary amine can be alkylated as with methyl iodide orphenethylbromide in a standard alkylation procedure to yield an N-alkyl(or substituted alkyl) derivative or may be acylated as bycyclopropylcarboxyl chloride to yield a 2-acyl derivative which can inturn be reduced as with lithium aluminum hydride to an alkyl yielding,in this instance, an N-cyclopropylmethyl derivative.

4a-Aryl-trans-dl-decahydroisoquinolines of Formula II below aredescribed in Belgian Pat. No. 802,557 and in a series of U.S. Pat. Nos.4,001,247; 4,001,248; 4,029,796 (each of which describes the preparationof both cis and trans- compounds); and U.S. Pat. No. 4,100,166, whichdescribes the preparation of certain cis- derivatives corresponding tothe trans- derivatives of the Belgian patent. ##STR2## wherein R and R¹have substantially the same meaning as hereinabove.

U.S. Pat. No. 4,001,247 describes several methods of preparingdecahydroisoquinolines. The first procedure begins with the reaction ofa 2-arylcyclohexanone with acrylonitrile to yield a2-phenyl-2-(β-ethyl)cyclohexanone. The nitrile group is hydrolyzed to acarboxylic acid function, the corresponding azide prepared and the azideconverted to the isocyanate. Treatment of the isocyanate with acidyields a 3a-aryl-2,3,3a,4,5,6,7-heptahydroindole. Next theheptahydroindole is acylated to yield a N-methyltetrafluoroboratequaternary salt. The reaction of this salt with diazomethane produces asalt of a 1-azonia-1-methyl-4-aryltricyclo[4,2,1,0¹⁻⁹ ]decane,rearrangement of which by treatment with heat and alkali produces a2-methyl-4a-aryl-2,3,4,4a,5,6,7,8-octahydroisoquinoline. The double bondin this compound can be hydrogenated to yield either a cis- ortrans-decahydroisoquinoline. In addition, the methyl group can beremoved to yield a secondary amine which can be realkylated to yield avariety of N-substituted-4a-aryldecahydroisoquinolines, as set forthabove for the corresponding 4a-aryloctahydro-1H-2-pyrindines.

A second reaction sequence disclosed in U.S. Pat. No. 4,100,166 involvesthe alkylation of a 2-arylcycloheptanone with bromoacetic ester to yielda 2-aryl-2-(ethoxycarbonylmethyl)cycloheptanone. This compound isformylated to yield a 7-formyl derivative, treatment of which withp-tosylazide yields the corresponding 7-azido compound. Treatment ofthis azido compound with methanol results in a molecular rearrangement,the ultimate product of which is a2-aryl-2-ethoxycarbonylmethylcyclohexanecarboxylic acid ester, isolatedas a mixture of cis- and trans-derivative. Saponification of the diesterfollowed by treatment with an acid chloride yields the correspondingcyclic anhydride named as a cis(ortrans)-3,4,4a,5,6,7,8,8a-octahydro-1,3-dioxo-1H-2-benzopyran. Thisintermediate is similar to those employed for the preparation of thepyrindines as described in Belgian Pat. No. 860,314 and the same seriesof reactions; i.e., reaction with a primary amine followed by reductionof the resulting imide, yields directly the cis (ortrans)-4a-aryl-N-substituted-decahydroisoquinoline.

Brittelli and Ripka in Belgian Pat. No. 802,557 disclose a stilldifferent method of preparing the 4a-aryldecahydroisoquinolines. Thisprocedure begins with a 2-cyano-3-aryl-3-ethoxycarbonylmethylcyclohexenewhich can be cyclized in the presence of acid to yield a4a-aryl-1,3-diox-1,2,3,4,4a,5,6,7-octahydroisoquinoline. This imide iscustomarily alkylated to yield an N-substituted product prior toreduction of the 8,8a-double bond (which produces a trans-derivative)and finally by removal of the dioxo groups by reduction with lithiumaluminum hydride. Reduction of the 8,8a-double bond can also take placeprior to reduction of the imide and thetrans-dioxo-decahydroisoquinoline can be epimerized to the correspondingcis derivative.

Each of the above synthetic procedures involves a large number of stepsand many of these steps afford the possibility of by-product formation.Furthermore, one of the procedures for preparing the abovedecahydroisoquinolines involves the use of the toxic and explosivesubstance, diazomethane. In addition, the procedures outlined above forthe preparation of the decahydroisoquinolines have been found to beinoperative for the preparation of octahydropyrindines.

It is an object of this invention to provide a short and simplifiedprocess for the preparation of either octahydropyrindines ordecahydroisoquinolines carrying an aryl substituent at the bridge-headcarbon, which synthesis can provide the desired products in either cis-or trans configuration.

SUMMARY OF THE INVENTION

In fulfillment of the above and other objects, this invention provides aprocedure for the preparation of 4a-aryloctahydropyrindines and4a-aryldecahydroisoquinolines containing the following reaction steps:

(1) reaction of phenyllithium (permissibly substituted at ameta-position) with a 1-alkyl or 1-benzyl-4-piperidone to yield thecorresponding 1-alkyl (or benzyl) 4-phenyl-4-hydroxypiperidine.

(2) dehydration to yield a 1-alkyl (orbenzyl)-4-(permissibly-substituted) aryl-1,2,3,6-tetrahydropyridine.

(3) reaction of the tetrahydropyridine thus formed with n-butyllithiumto form a carbanion and reacting said carbanion with a propylene orbutylene dihalide of the formula ##STR3## wherein each Y is H, CH₃ or C₂H₅, n is 3 or 4 and X and X' are chlorine, bromine or iodine to yield a1-alkyl (orbenzyl)-4-(permissibly-substituted)aryl-4-(ω-haloalkyl)-1,4,5,6-tetrahydropyridine.

(4) internal cyclization of the alkylated tetrahydropyridine using, forexample, sodium iodide in dilute acetonitrile solution to provide thecorresponding 2-alkyl(or benzyl)-4a-(permissibly-m-substituted)aryl-3,4,4a,5,6,7-hexahydro-2-pyrindine or2,3,4,4a,5,6,7,8-octahydroisoquinoline of the formula: ##STR4## whereinR is (C₁ -C₃)alkyl, (C₃ -C₄)cycloalkylmethyl, benzyl or phenethyl, R¹ isH or (C₁ -C₃)alkyloxy, Z is ##STR5## or a direct bond and each R² and Yis independently H or (C₁ -C₂)alkyl.

(5) followed by hydrogenation to yield either a cis- ortrans-octahydropyrindine or decahydroisoquinoline of the formula:##STR6## wherein R, R¹, R², Y and Z have the same meaning ashereinbefore.

The term (C₁ -C₃)alkyl includes methyl, ethyl and propyl and the term(C₃ -C₄)cycloalkyl, cyclopropyl and cyclobutyl.

This invention is more graphically illustrated by the following ReactionScheme. ##STR7##

In the above Reaction Scheme, R, R¹, R², X, X', Y and retain theirprevious significance and m is 0 or 1.

According to Reaction Scheme I, an N-alkyl(or benzyl) 4-piperidone,permissibly substituted at carbons 2 or 6 of the piperidone ring withone or more methyl or ethyl groups, is reacted with phenyllithium orm-methoxyphenyllithium to yield an N-alkyl(or benzyl)4-phenyl-4-hydroxypiperidone, permissibly substituted with ethyl ormethyl at carbons 2 and 6 (II). Phenyllithium or 3-methoxyphenyllithiumis prepared by reaction of the corresponding bromobenzene or3-methoxybromobenzene with n-butyl lithium in an inert, preferably ahydrocarbon, solvent. In this reaction, the lithium and bromine atomsinterchange to yield n-butylbromide as a by-product plus the desiredphenyllithium or 3-methoxyphenyllithium. A solution of the piperidone inan inert hydrocarbon solvent or ethereal solvent is added thereto andthe reaction carried out simply by stirring at ambient temperature.

The 4-hydroxypiperidine thus formed is next dehydrated to yield thecorresponding 1,2,5,6,tetrahydropyridine(XII). This dehydration can beaccomplished by treating the tertiary hydroxy compound with adehydrating agent such as phosphorus pentoxide in a solvent such asmethanesulfonic acid. Alternatively, the dehydration can be accomplishedby reacting the tertiary hydroxyl-containing piperidine with a catalyticquantity of a strong acid such as p-toluenesulfonic acid, also in aninert solvent.

Next, the N-alkyl(or benzyl) 4-phenyl(or m-methoxyphenyl)1,2,5,6-tetrahydropyridine is alkylated with a 1,3-dihalopropane or a1,4-dihalobutane representated by the structure ##STR8## in which X andX' are the same or different halogens of the group consisting ofchlorine, bromine and iodine, each Y is independently hydrogen, methylor ethyl and m is 0 or 1. The product of this reaction is an N-alkyl(orbenzyl)-4-phenyl(orm-methoxyphenyl)-4-haloalkyl-1,4,5,6-tetrahydropyridine permissiblysubstituted with one or more methyl or ethyl groups at C-2, or C-6(XIV). In the alkylation reaction, the most reactive halogen of thedihaloalkane will react preferentially at the 4 position of thepyrindine ring. If the alkylating agent (XIII) is unsubstituted; i.e.,all Y's are hydrogen, the alkyl group may have the same halogen atoms ateach end of the chain. For example, in such a case, the alkylating agentcould be a 1,3-dibromopropane or a 1,4-dichlorobutane. The samesituation would be present if any symmetrical alkylating agents is usedas for example 1,3-dibromo-2-methylpropane or1,4-dibromo-2,3-dimethylbutane as well as 1,3-dibromopropane etc. Ingeneral, however, I prefer to employ alkylating agents in which X and X'do represent different halogen atoms. We have found that the use ofhalogens of different reactivity tends to minimize dimer formation evenin a symmetrical alkane. In other words, use, for example, of a1,3-diiodopropane might result in product of a significant amount of anundesired by-product in which two pyridines are linked through a propanegroup at C-4. By employing an alkylating agent in which the halogensatoms are different, our preferred mode, the reaction conditions whichwill suffice to cause a reaction to the place between the iodo group ina 1-iodo-3-bromopropane, for example, to cause it to react at C-4 of thepyridine would not be sufficiently stringent to cause any large quantityof the resulting omega-bromopropyl derivative to react with a secondmolecule of the pyridine to yield a "dimeric" by-product. It is, ofcourse, true that a dimerization reaction can be minimized by utilizinglow reaction temperature or dilute solutions or both and by adding thetetrahydropyridine compound to a solution of the alkylating agent--thedihaloalkane. During of the alkylation at C-4, the 3, 4 double bondmigrates to the 2, 3-position to yield an enamine. We customarily carryout the alkylation by reacting the tetrahydropyridine (XII) with n-butyllithium, thus forming a carbanion at C-2. This carbanion is part of anallylic system and can quickly rearrange to yield a carbanion at C-4,the C-4 carbanion being energetically more stable. It is probably duringthe formation of the carbanion that the double bond migration referredto above takes place.

Finally, the alkylated enamine (XIV) is internally cyclized in thepresence of sodium iodide in a dilute acetonitrile solution to yield ahexahydropyrindine or octahydroisoquinoline, depending upon the value ofthe "Z".

Internal alkylation by the C-4 ω-haloalkyl group takes place on theadjacent carbon at C-3, leaving the double bond in the same relativeposition in the pyrindine and isoquinoline as it was in thetetrahydropyridine starting material.

This invention is further illustrated by the following specificexamples:

EXAMPLE 1 1-Methyl-4-hydroxy-4-(3-methoxyphenyl)piperidine

A solution of 159 ml. of n-butyl lithium in 100 ml. of hexane containing47.7 g. of 3-methoxybromobenzene was stirred at -25° C. for twentyminutes and then was warmed to room temperature at which temperature itwas stirred for one hour, thus providing 3-methoxyphenyllithium. Thereaction mixture was chilled to 10° C. and stirred while a solutionof 50g. of 1-methyl-4-piperidone in 100 ml. of diethyl ether was added indropwise fashion over a thirty minute period. Following the completionof the addition, the reaction mixture was stirred for two additionalhours, and was then mixed with 50 ml. of saturated aqueous sodiumchloride solution. The aqueous solution was extracted several times withdiethyl ether, and the ethereal extracts were combined and concentratedto drynessto provide 38 g. of1-methyl-4-hydroxy-4-(3-methoxyphenyl)piperidine formedin the abovereaction.

EXAMPLE 2 1-Methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine

To a stirred solution of 200 ml. of 50 g. of phosphorous pentoxide inmethanesulfonic acid was added portionwise over four minutes 59 g. of1-methyl-4-hydroxy-4-(3-hydroxyphenyl)piperidine. The reaction wasexothermic, the temperature rising to 70° C. After complete addition ofthe piperidine derivative, the reaction mixture was poured onto 200 g.of ice, and the resulting aqueous mixture made alkaline by theadditionof ammonium hydroxide. The alkaline mixture was extracted several timeswith diethyl ether, and the ethereal extracts were combined, washed withwater, dried, and the solvent removed by evaporation under reducedpressure to provide 44.7 g. of an oil. The oil was distilled to provide1-methyl-4-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine; B.P.=123°-138°C. at 0.1 torr.

Analysis Calc. for C₁₃ H₁₇ NO Theory: C, 76.81; H, 8.43; N, 6.89.Found:C, 76.52; H, 8.15; N, 6.67.

EXAMPLE 3 4a-Phenyl-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine

To a stirred cold (-5° to -10° C.) solution of 25 g. of1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in 450 ml. oftetrahydrofuranwas added dropwise over thirty minutes 90 ml. of 1.6molar n-butyllithium in hexane. Following completion of the addition,the solution was stirred for ten minutes at -10° C. and then cooled to-30° C. The cold solution next was added in dropwise fashion over atwenty minute period to a stirred solution of 73.3 g. of3-chloropropylbromide in 300 ml. of diethyl ether chilled to -50° C.Following completion of theaddition, the reaction mixture was warmed to-20° C. and diluted with 500 ml. of saturated aqueous sodium chloridechilled to 0° C. The organic layer was separated, washed with water, andthe desired product was extracted therefrom with 1200 ml. of 1 Nhydrochloric acid. The aqueous acidic layer was washed with diethylether and the ether extracted discarded. The acidic aqueous solution wasthen made alkaline bythe dropwise addition of concentrated aqueoussodium hydroxide. The resulting alkaline solution was extracted severaltimes with diethyl ether, and the ethereal extracts were combined,washed with water and dried. Evaporation of the solvent at 10° C.afforded an oil which was dissolved in 2500 ml. of acetonitrilecontaining 52.5 g. of sodium iodide. The reaction mixture was heated atreflux temperature with stirring for twenty-four hours, after which timethe solvent was removed by evaporation under reduced pressure. The crudeproduct thus formed was dissolved in a mixture of 800 ml. of 1 N sodiumhydroxide and 1000 ml. of diethyl ether, and the mixture was stirredvigorously for forty-five minutes. The ethereal layer then wasseparated, washed with saturated aqueous sodium chloride and dried.Removal of the solvent by evaporation under reduced pressure affordedthe product as an oil, which, upon distillation, provided 21.5 g. of4a-phenyl-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine; B.P.=110°-112° C.at 0.075 torr.

Analysis Calc. for C₁₅ H₁₉ N Theory: C, 84.46; H, 8.98; N, 6.57. Found:C, 84.74; H, 8.72; N, 6.28.

EXAMPLE 4

Following the procedure of Example 3,1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine was reacted with3-chloropropylbromide and the resulting 4-(ω-haloalkyl derivativecyclized with sodium iodide to afford4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine;B.P.=132°-134° C. at 0.1 torr.

Analysis Calc. for C₁₆ H₂₂ NO Theory: C, 78.97; H, 8.70; N, 5.76.Found:C, 76.58; H, 8.28; N, 5.36.

m/e: theory 243; found 243.

EXAMPLE 5trans-4a-Phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine

A solution of 5.0 g. of4a-phenyl-1-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine in 50 ml. ofethanolcontaining 500 mg of platinum oxide was stirred at roomtemperature for four hours under a hydrogen atomsphere of 60 p.s.i. Thehydrogenation mixture was filtered to remove the catalyst and thefiltrate concentrated by evaporation to provide an oil which was shownby NMR and high pressure liquid chromatography to consist of about fortypercentcis-4a-phenyl-1-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine andabout sixty percent of the corresponding trans isomer. The mixture wasdissolved in 50 ml. of diethyl ether and the resulting solution madeacidic by the addition of a saturated solution of hydrogen bromidedissolved in diethyl ether. Concentration of the ethereal solutioneffected crystallization of a hydrobromide salt. The salt was filteredandthe precipitate recrystallized from 30 ml. of isopropanol and 70 ml.of diisopropyl ether to afford 2.6 g. ofcis-4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindiniumbromide.

The filtrate was evaporated to dryness and the resulting residuedissolved in water. The aqueous solution was made alkaline by theaddition of 1 N aqueous sodium hydroxide, and the aqueous alkalinesolution was extracted with diethyl ether. The ethereal extracts werecombined, washed with waterand dried. Removal of the solvent byevaporation under reduced pressure afforded 2.57 g. oftrans-4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine.

The trans-pyrindine derivative was dissolved in 120 ml. of ethanol andreacted with 2.76 g. of picric acid to provide 2.7 g. oftrans-4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindiniumpicrate; M.P.=167°-168° C.

Analysis Calc. for C₂₁ H₂₄ N₄ O₇ Theory: C, 56.75; H, 5.44; N, 12.61.Found: C, 56.99; H, 5.65; N, 12.46.

The corresponding maleate salt was prepared in similar fashion.trans-4a-Phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindiniummaleate. Melted at 113°-114° C.

Analysis Calc. for C₁₉ H₂₅ NO₄ Theory: C, 68.86; H, 7.60; N,4.23. Found:C, 68.66; H, 7.82; N, 3.98.

EXAMPLE 6

Following the procedure set forth in Example 5,4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine washydrogenated over platinum oxide to provide a 60:40 mixture oftrans-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindineand the corresponding cis-isomer. The trans isomer was crystallizedasthe picrate salt. The cis isomer was isolated as the free base, namelycis-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine;M.P.=40°-43° C.

Analysis Calc. for C₁₆ H₂₃ NO Theory: C, 78.32; H, 9.45; N, 5.71.Found:C, 78.26; H, 9.31; N, 5.61.

EXAMPLE 7 1-Methyl-4a-phenyl-2,3,4,4a,5,6,7,8-octahydroisoquinoline

Following the procedure of Example 3, 25 g. of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was dissolved in 450 ml. ofTHF. The solution was cooled and 90 ml. of a 1.6 molar n-butyllithiumsolution in hexane added thereto in dropwise fashion. Next, 8.23 g. of1-bromo-4-chlorobutane were added as a chilled solution. As the additionwas carried out, the temperatures rose to about 20° C.1-Methyl-4-phenyl-4-(ω-chlorobutyl-1,4,5,6-tetrahydropyridine, theproduct of the reaction, was isolated by the procedure of Example 3 andwas dissolved, without further purification, in 2500 ml. of acetonitrilecontaining 52.5 g. of sodium iodide. The reaction mixture was heated torefluxing temperature for about 1 day and the product of the reaction,1-methyl-4a-phenyl-2,3,4,4a,5,6,7,8-octahydroisoquinoline, was isolatedbythe procedure of Example 3 and purified by distillation. The compounddistilled in the range 115°-120° C. at 0.05 torr.; yield=17.6 g.

Analysis Calc. for C, 84.53; H, 9.31; N, 6.16 Found: C, 84.26; H, 9.12;N, 6.23.

Following the above procedure but substituting1-methyl-4-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine for1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, there was prepared1-methyl-4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,8-octahydroisoquinoline.The compound distilled in the range 144°-6° C. at 0.1 torr.; yield 19.3g.

Both the above octahydroisoquinolines can be hydrogenated to yield thecorresponding cis and trans decahydroisoquinolines.

The novel process of this invention has been illustrated with respect tocompounds in which R is methyl, but is readily apparent to those skilledin the art that R could be any group not susceptible to hydrogenationincluding ethyl, cyclo butylmethyl, cyclopropylmethyl, benzyl and thelike.

Compounds prepareable by the processes of this invention are analgeticspossessing also to a greater or lesser degree both analgesic agonist andantagonist properties. In addition, compounds in which R is methyl orbenzyl can be transformed by standard procedures into compounds in whichRis ethyl, n-propyl, cyclopropylmethyl and the like as well as groupsnot coming within the scope of R in the above formula, including groupswhich are susceptible to hydrogenation such as allyl, 2-methylbutenyland the like.

In addition, the above procedure has been illustrated with respect tocompounds of which R¹ is an alkoxy group. The final octahydropyridineanddecahydroisoquinoles in which R¹ is alkoxy are also useful intermediatesin that they can be demethylated to yield the corresponding compounds inwhich R¹ is hydroxy. These 4a-meta-hydroxyphenyl derivatives are ingeneral more powerful analgesic-antagonist or agonist compounds in theoctahydropyridine and decahydroisoquinoline series than thecorresponding methoxy derivatives.

We claim:
 1. An intermediate of the formula ##STR9## in which R is (C₁-C₃)alkyl, (C₃ -C₄)cycloalkylmethyl, benzyl or phenethyl, R¹ is H or (C₁-C₃)alkyloxy, each R² and Y is independently H, CH₃ or C₂ H₅, m is 0 or1 and X' is Cl, Br or I.